Treatment of tumors by interstitial implantation of radioactive material has been utilized since shortly after the discovery of radioactivity. Within the last decade, interest in this treatment modality has been revitalized due to prospects of enhancement when combine with hyperthermia or chemotherapy and advances in technology. The goal of this project is to determine optimal biological conditions which will lead to improvement of methods for treating tumors with encapsulated radioisotopes in combination with hyperthermia. In reaching this goal, an understanding of the biological effects of selected applications of ionizing radiation related to brachytherapy in rodent and human cell types in culture and in a rodent tumor model will be determined. The primary goal is to determine whether extended low temperature hyperthermia (40oC-42oC) is superior to acute high temperature exposures (>43oC) in sensitizing low dose rate irradiation. Heating during irradiation at dose rates between 0.05 and 5 Gy/Hr will be investigated to determine the range in which 40oC-42oC is effective. The thermal enhancement ratios of 125l and 192lr, whose photon energies are 30 keV to 330 keV respectively, at low dose rate will be determined to see if hyperthermia is less effective in conjunction with 125l. The biological response to radiation pulsing, which will mimic a new brachytherapy technique utilizing scanning of an isotope source, will be compared to continuous irradiation as is applied currently. Initially, rat 9L gliosarcoma cells will be used to determine the cell specific responses to the above exposures. A normal human cell line and 2 human tumor cell types will be investigated to determine if our conclusions are confirmed in cells of human origin. Cell survival, cell cycle distribution and proliferation rate will be measured. The role of inhibition of potentially lethal damage repair by low temperature hyperthermia will also be investigated in vitro. The 9L cells while growing as subcutaneous tumors in Fisher 344 rats will be treated and analyzed in vivo to determine the dependence of cytotoxic effects on the in situ environmental factors. The animal models will extend our knowledge beyond the cellular aspects to that of the complex responses of tumor cells within their host and the role of interstitial radiation-hyperthermia damage in these processes. These cell and animal model data will provide a better understanding of the biological effects of isotope type, dose rate, and hyperthermic conditions, thus enhancing our ability to develop better clinical brachytherapy methods.